9/29/2016 PPI Trivia • What year were PPIs introduced in the U.S.? Should we heed the renal failure warnings associated with proton • First PPI marketed in the U.S.? pump inhibitors (PPIs)? Mary Vilay, PharmD • What year did PPIs become available OTC? (mvilay@salud.unm.edu) NMSHP Balloon Fiesta Symposium October 3, 2016 76 year old female 76 year old female • HTN – treated with • Experiencing increasing • Labs: • Urinalysis: amiloride and HCTZ for generalized malaise, fatigue, – Hct 33.2% – pH 6.5 several years anorexia x 2 wk – WBC 10.3x10 3 /uL – Specific gravity 1.006 • Reflux esophagitis x 1 yr • Patient d/c amiloride and – Na 136 mmol/L – Trace protein HCTZ x 5 days – Initially treated with famotidine 20 mg daily, but – K 4.7 mmol/L – 35 WBCs/hpf • Presents to hospital developed recurrent – Cl 103 mmol/L – No renal tubular epithelial • BP 120/60, HR 70 (lying) esophageal ulceration with cells stricture – CO 2 17 mmol/L • BP 84/56; HR 110 (standing) – 6 mo ago, Rx omeprazole 20 – No red blood cells – BUN 84 mg/dL (19 mg/dL) • Good skin turgor mg daily, which was increased – Wright’s stain – 6% – SCr 7.2 mg/dL (1.2 mg/dL) to 40 mg daily • Moist mucous membranes eosinophils – Responded well, sx ‐ free x 3 – Ca 8.3 mg/dL • No skin rashes mo, omeprazole dose • Renal Ultrasound • No flank tenderness – Phosphate 6.1 mg/dL lowered to 20 mg daily – No hydronephrosis – Albumin 2.9 g/dL Ruffenack. Am J Med 1992;93:472. Ruffenack. Am J Med 1992;93:472. PPI associated with a number of adverse effects Could pills for heartburn give you kidney problems? Proton pump inhibitors (PPIs) may come with worrying health effects 1
9/29/2016 Presentation Objectives Pharmacists 1. Describe how PPIs cause acute kidney injury. 2. Evaluate recent studies demonstrating association between PPIs & renal injury. 3. Formulate recommendations about PPI given the recent evidence. Technicians Lazarus B, et al. JAMA Intern Med 2016 Feb; 176(2): 238 ‐ 46 1. List renal effects associated with PPIs. 2. State limitations of recent studies investigating renal PROTON PUMP INHIBITOR USE AND effects of PPIs. THE RISK OF CHRONIC KIDNEY DISEASE 3. Specify alternative medications for PPIs that are not associated with kidney injury. Lazarus et al Study Design Aric Population ‐ based Cohort • 15,792 adults • Participants monitored • Objective: quantify association between PPI use via: – 45 to 64 years old and incident kidney disease in general population – Prospectively recruited – Annual telephone survey • Forsyth, NC – Reviewed community • Secondary outcome: evaluate association • Jackson, MS hospital discharge lists between PPI use and AKI • Suburban Minneapolis, MN – Until Dec. 31, 2011 • Washington County, MD • Deaths identified by: • Observational cohort study – Telephone survey of • Data sources alternative contacts – Surveillance of public – Atherosclerosis in Risk in Communities (ARIC) study records: newspaper obituaries, state death – Geisinger Health System lists, & death certificates from Dept of Vital Statistics Participants for PPI Study = ARIC Study Participants for PPI Study = ARIC Study Visit 4 Participants Visit 4 Participants • Visit 4 conducted Feb. 1, 1996 to Jan 30,1999 (N=11,656) • Visit 4 conducted Feb. 1, 1996 to Jan 30,1999 • CKD Analysis • Visit 4: N=11,656 – ACR first obtained at this visit & few patients took PPI before 1996 • AKI analysis: excluded persons with known – Exclusion: missing eGFR or UACR (n=215); eGFR <60 (CKD ‐ EPI) (n=725) ESRD or eGFR <15 • Missing data for education, health insurance status, cigarette smoking, BMI, mean resting SBP, use of antihypertensive or anticoagulant – N=11,145 medications, prevalent hypertension, DM, cardiovascular disease (n=234) – N=10,482 • Dates of study analysis: Feb 1, 1996 to Dec 31, 2011 – Median follow up = 13.9 y 2
9/29/2016 How were outcomes determined? Measurement of PPI in ARIC • PPIs and H2RAs measured at baseline visit (Jan • Incident CKD defined by diagnostic codes that 1987 to March 1990) via direct visual inspection indicated CKD at hospital discharge (ICD ‐ 9) or of pill bottles for all medication used in the death (ICD ‐ 10) or by incident ESRD (linkage with preceding 2 weeks USRDS) • Subsequent PPI & H2RA exposure obtained during annual telephone follow ‐ up • Incident AKI defined by hospitalization or death • 2006 onward, participants asked to assemble all – ICD ‐ 9 & ICD ‐ 10 codes for acute kidney/renal failure medications and to “read names of all • Participants who died before developing CKD, medications prescribed by a doctor” were lost ‐ to follow ‐ up or had disease ‐ free • Exposure to other medications similarly survival were censored measured Replication Cohort Geisinger Analysis • Incident CKD = 1 st outpatient eGFR <60 sustained at • Geisinger Health System = large rural health subsequent eGFR assessments or development ESRD care system in central & NE Pennsylvania (linkage to USRDS) • Incident AKI = ICD ‐ 9 code and death (linkage to • Receiving care Feb 13, 1997 to Oct 9, 2014 National Death Index) • Out ‐ patient eGFR ≥ 60 • Individuals who did not develop outcomes censored at last follow ‐ up or death • Selection based on earliest time point with • Medication use determined by prescriber Rx within 90 both SCr and SBP available days before baseline • PPI frequency categorized as daily or BID (assumed to • N=248,751 be daily if not specified) – Median follow up 6.2 years • Comorbidities captured by billing codes (in ‐ pt & out ‐ pt) ARIC Baseline Characteristics ARIC Baseline Characteristics Variable PPI Users H2RA Users Non ‐ Users P ‐ value Variable PPI Users H2RA Users Non ‐ Users P ‐ value Age 62.8±5.5 63.1±5.5 62.5±5.6 0.008 Mean BMI 29.4 (5.3) 29.4 (5.8) 28.7( (5.6) <0.001 Male 42.5% 39.3% 44.4% 0.01 SBP 126.5±18.3 128.2±18.6 127±18.8 NS White 86% 84.2% 77.9% <0.001 HTN 54.3% 50% 44.8% <0.001 Education ≥ 12 y 81.7% 79.4% 81.8% NS DM 14.9% 18% 15.6% NS Health Insurance 92.2% 88.9% 85.6% <0.001 CVD 13.7% 14.1% 10.9% 0.003 Mean eGFR 87.8±13.4 86.5±13.5 88.9±13.1 <0.001 Medications UACR 4 (2 ‐ 7.5) 3.6 (1.8 ‐ 7.1) 3.7 (1.7 ‐ 7.5) NS Antihypertensive 55.3% 48.5% 39.9% <0.001 Cigarette Smoker ACE ‐ I/ARB 16.8% 13.4% 12.9% NS Current 11.5% 15.5% 15.2% Diuretic 16.1% 12.1% 9.6% <0.001 Former 48.4% 44.2% 43.2% NS Aspirin 64.9% 67.6% 54.9% <0.001 Never 40.1% 40.3% 41.6% NSAID 27.6% 32.8% 33.2% NS Statin 20.2% 13.6% 10.3% <0.001 Anticoagulant 1.9% 2.8% 1.7% 0.04 3
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